A high proportion, perhaps 1%, of all nucleotides in most outbreeding organisms, including humans, mice and Drosophila, are heterozygous in an average individual. The relative roles of mutation, migration and natural selection in determining these polymorphisms is the fundamental issue in population genetics. The roles of migration versus selection in determining the geographic cline in allozyme frequencies at the alcohol dehydrogenase locus in Drosophila melanogaster are being tested by comparing the distribution of the DNA sequence haplotype variants in many populations with that predicted by several theoretical models of migration effects on gene frequency. The molecular genetic variation in the white locus in Drosophila has also been measured in great detail. The relationships of the amounts and types (base pair substitutions, deletions, etc.) of variation to the structure and function of the gene are the primary focus of investigation. Duplications of the metallothionein gene in Drosophila are known to afford resistance of heavy metal toxicity. The frequencies and properties of these duplication in relationship to environmental levels of heavy metals are being investigated.